Olefin ring closing metathesis and hydrosilylation reaction in aqueous medium by grubbs second generation ruthenium catalyst

Article abstract of DOI:10.1021/jo801330c

(Chemical Equation Presented) The Grubbs second generation ruthenium catalyst was shown to catalyze various olefin ring closing metathesis and hydrosilylation reactions in aqueous medium. Reactions proceeded in pure water without any additives or cosolvents, in a short period of time. We found that inhomogeneity of the reaction mixture does not prevent high conversion (70-95%) of the products in both reactions.

Full text of DOI:10.1021/jo801330c

Olefin Ring Closing Metathesis and
Hydrosilylation Reaction in Aqueous Medium by
Grubbs Second Generation Ruthenium Catalyst
Vivek Polshettiwar and Rajender S. Varma*
Sustainable Technology DiVision, National Risk Management
Research Laboratory, U.S. EnVironmental Protection
Agency, MS 443, Cincinnati, Ohio 45268
FIGURE 1. Grubbs second generation ruthenium catalyst.
thesis4 and green chemistry.7 Although there are few protocols
for olefin metathesis reactions in aqueous medium,8-11 surpris-
ingly to the best of our knowledge there is no description of
the hydrosilylation reaction in aqueous medium. Pioneers in this
field, Grubbs et al., prepared water soluble N-heterocyclic-
carbene-based olefin metathesis ruthenium catalyst.9 Although
this work led the way to advance the metathesis reaction in
aqueous medium, the reaction still needs 12-24 h to complete.
Blechert et al. used Grubbs second generation ruthenium catalyst
for the RCM reactions; however, they used a mixture of organic
solvents and water with extended reaction time.10 Recently,
Raines and co-workers reported olefin metathesis in homoge-
neous aqueous medium using second generation Hoveyda-
Grubbs catalyst and claimed it as a green protocol.11 They did
not use pure water as a reaction medium; instead they used
organic solvents with some percentage of water in it and very
often deuterated solvents, which does not justify the protocol
to be truly environmentally friendly. Thus, the majority of the
reported aqueous RCM methods used a mixture of organic
solvent and small amounts of water or expensive and toxic
deuterated solvents, e.g., C6D6, as cosolvents with exotic
ruthenium complexes as catalysts. Consequently, we decided
to develop simple and environmentally benign RCM and
hydrosilylation protocols exclusively in aqueous medium.
Engaged in the development of greener synthetic pathways,12
herein we report an expeditious and benign ring-closing
metathesis in pure aqueous medium (without using any organic
or deuterated solvent) with conventional Grubbs second genera-
tion ruthenium (G-2) catalyst (Figure 1).
Varma.rajender@.epa.goV; polshettiwar.ViVek@epa.goV
ReceiVed June 19, 2008
The Grubbs second generation ruthenium catalyst was shown
to catalyze various olefin ring closing metathesis and
hydrosilylation reactions in aqueous medium. Reactions
proceeded in pure water without any additives or cosolvents,
in a short period of time. We found that inhomogeneity of
the reaction mixture does not prevent high conversion
(70-95%) of the products in both reactions.
The advent of Grubbs catalyst has fueled the widespread
application for various organic transformations, importantly
olefin metathesis1 and very recently hydrosilylation reaction.2
Olefin metatheses, such as ring-closing metathesis (RCM) and
cross-metathesis (CM), are extensively used as a dominant tool
for the carbon-carbon bond forming reaction in the synthesis
of several small molecules,3 biomolecules,4 and macromol-
ecules5 in the drug discovery and polymer industry. Similarly,
the hydrosilylation reaction of alkynes to generate vinylsilanes,
powerful intermediates in organic synthesis,6 is a simple and
widely used protocol.
(6) Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.; Kakiuchi,
F.; Murai, S. J. Org. Chem. 2000, 65, 1475–1488.
(7) (a) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 6786–6801. (b) Cornils, B.; Herrmann, W. A.
Aqueous-Phase Organometallic Catalysis, 2nd ed.; Wiley-VCH: Weinheim,
Germany, 2004.
(8) (a) Gułajski, L.; Sledz, P.; Lupa, A.; Grela, K. Green Chem. 2008, 10,
271–274. (b) Gułajski, L.; Michrowska, A.; Naroønik, J.; Kaczmarska, Z.;
Rupnicki, L.; Grela, K. Chem. Sus. Chem. 2008, 1, 103–109. (c) Lipshutz, B. H.;
Ghorai, S.; Aguinaldo, G. T. AdV. Synth. Catal. 2008, 350, 953–956. (d) Lipshutz,
B. H.; Ghorai, S.; Aguinaldo, G. T. Org. Lett. 2008, 10, 1325–1328. (e) Davis,
K. J.; Sinou, D. J. Mol. Catal. A: Chem. 2002, 177, 173–178. (f) Li, C.-J.; Wang,
D.; Chen, D.-L. J. Am. Chem. Soc. 1995, 117, 12867–12868.
(9) Jordon, J. P.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 5152–
5155.
Both of these reactions are generally carried out in organic
solvents and their potential utility in aqueous medium is largely
untapped, despite their profound allure for biomolecule syn-
(10) Connon, S. J.; Rivard, M.; Zaja, M.; Blechert, S. AdV. Synth. Catal.
(1) (a) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765. (b) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
2003, 345, 572–575.
(11) Binder, J. B.; Blank, J. J.; Raines, R. T. Org. Lett. 2007, 9, 4885–4888.
(12) (a) Polshettiwar, V.; Varma, R. S. Chem. Soc. ReV. 2008, 37, 1546-
1557. (b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629–639.
(c) Polshettiwar, V.; Varma, R. S. Curr. Opin. Drug DiscoVery DeV. 2007, 10,
723–737. (d) Polshettiwar, V.; Varma, R. S. J. Org. Chem. 2007, 72, 7420–
7422. (e) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006, 71, 6697–6700.
(f) Ju, Y.; Varma, R. S. J. Org. Chem. 2006, 71, 135–141. (g) Ju, Y.; Varma,
R. S. Org. Lett. 2005, 7, 2409–2411. (h) Polshettiwar, V.; Varma, R. S.
Tetrahedron 2008, 64, 4637–4643.
(2) (a) Trost, B. M.; Ball, Z.-T. Synthesis 2005, 85, 3–887. (b) Arico, C. S.;
Cox, L. R. Org. Biomol. Chem. 2004, 2, 2558–2562. (c) Maifeld, S. V.; Tran,
M. N.; Lee, D. Tetrahedron Lett. 2005, 46, 105–108.
(3) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
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10.1021/jo801330c CCC: $40.75
Published on Web 08/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7417–7419 7417

TABLE 1. Optimization of Reaction Conditions with G-2 in
Water
TABLE 2. RCM Reaction of Dienes Catalyzed by G-2 in Watera
entry
G-2
temp (°C)
reaction time (h)
conversion (%)
1
2
3
4
5
1 mol %
2 mol %
4 mol %
4 mol %
4 mol %
rt
rt
rt
45
45
6
6
6
1
35
55
90
80
95
1.5
Initially the RCM reaction of diethyl 2,2-diallylmalonate with
Grubbs second generation ruthenium catalyst in aqueous
medium was investigated to establish the feasibility of our
strategy and to optimize the reaction conditions (Table 1).
First the reaction was conducted with 1 mol % of catalyst
and a moderate 35% conversion was observed at room tem-
perature (rt). As the catalyst amount was increased to 4 mol %,
a good conversion (90%) was achieved in 6 h. However, when
the mixture was warmed at 45 °C, the reaction proceeded
expeditiously with 80% conversion within 1 h, which was
further increased to 95% by extending the reaction time by
another 30 min.
With the above optimized reaction conditions, ring-closing
metathesis of a series of dienes with Grubbs second generation
ruthenium catalyst was probed solely in aqueous medium (Table
2). A variety of substrates such as diallylamines (entries 1-4),
diallyl ether (entry 5), and diallyl thioether (entry 6) were
successfully metathesized to from respective cyclic products
with high conversion.
Excellent conversions were observed for various N-substituted
allylamines within 2 h. In the case of diallyl ether and thioether,
although the conversion is high, the decrease in yield is due to
volatility of the ensuing cyclic products. The pyrimidine-based
diene (entry 8), an extensively used building-block in drug
discovery, also underwent RCM reaction in aqueous medium
with high yield, proving the suitability of this protocol for
assembly of biomolecules.
While metathesis remains the most imperative application for
the Ru-catalyst, a growing number of other reactions are also
mediated by this procedure. Selective formation of the ꢀ-(E)
isomer of vinylsilane by hydrosilylation of alkyne has proven
to be a difficult task,2 and in view of the fact that hydrosilylation
reaction has not been reported in aqueous medium, we set out
to attempt the regioselective hydrosilylation of alkyne in aqueous
medium using G-2. Selective formation of the ꢀ-(E) isomer of
a range of vinylsilanes in high yields occurred with use of this
protocol and the results are summarized in Table 3.
Grubbs second generation ruthenium catalyst was found to
be capable of catalyzing these reactions in water, achieving good
conversion. We observed that warming equimolar quantities of
alkyl silane and alkynes at 50 °C in aqueous medium in the
presence of G-2 resulted in the rapid consumption of starting
materials (as monitored by GC-MS and 1H NMR). The reaction
was complete within 4 h in the case of triethylsilane and was
complete in 6 h for triphenylsilane. Among the three isomeric
vinylsilane products, namely ꢀ-(Z), ꢀ-(E) and R, the predominant
regioselective formation of the ꢀ-(E) isomer as a major product
was very satisfying. Heterocyclic 6-ethynylquinoxaline also
reacts efficiently with triethylsilane yielding corresponding
a Reactions were performed at 45 °C with 4 mol % catalyst G-2 in
water for 2 h. b GC yield.
silylated product in 80% yield. An attempt to hydrosilylate
2-ethynylpyridine was not successful, which may be due to its
instability under our reaction conditions. Aliphatic alkynes can
also be hydrosilylated; however, due to competitive metathesis
reaction, a mixture of products was formed.
In conclusion, we have developed a simple and sustainable
protocol for olefin ring closing metathesis and selective hy-
drosilylation reactions that proceed exclusively in aqueous
medium without any additives or cosolvents. It is remarkable
that the inhomogeneity of the reaction mixture does not prevent
high conversion of the products in both reactions. These
reactions will be very useful in drug discovery as various
biomolecules, enzymes, and polysaccharides have stronger
affinity toward water than organic solvent and can be easily
metathesized and hydrosilylated. Also, the use of commercially
available Grubbs second generation ruthenium complex as a
catalyst and mild reaction conditions are additional eco-friendly
attributes of this aqueous protocol.
7418 J. Org. Chem. Vol. 73, No. 18, 2008

TABLE 3. Hydrosilylation of Alkynes Catalyzed by G-2 in Watera
mixture was quenched with ether and product was purified by
column chromatography.
Spectral data of a representative compound are given below.
2,5-Dihydro-1-tosyl-1H-pyrrole. 1H NMR (300 MHz, CDCl3):
δ 2.38 (3H, s), 4.21 (4H, s), 5.45 (2H, s), 7.35 (2H, d), 7.81 (2H,
d) ppm. 13C NMR (CDCl3): δ 21.5, 54.8, 125.4, 127.4, 129.7, 134.4,
143.3 ppm. MS: (M+) 223, 155, 139, 91, 68, 51, 41. Anal. Calcd
for C11H13NO2S: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.12; H,
5.80; N, 6.19.
A typical experimental procedure for hydrosilylation reaction of
alkyne follows: The alkyne (1 mmol), silane (1 mmol), and Grubbs
second generation ruthenium catalyst (4 mol %) were added to a
10 mL glass tube filled with 2 mL of water and the reaction mixture
was stirred at 50 °C. The reaction was complete within 4 h in the
case of triethylsilane and was complete in 6 h for triphenylsilane.
After completion of the reaction, the reaction mixture was quenched
with ether and product was purified by column chromatography.
Spectral data of a representative compound are given below.
1
ꢀ-(E)-Triethyl(styryl)silane. H NMR (300 MHz, CDCl3): δ
0.52 (6H, m), 0.95 (9H, m), 5.79 (1H, d, J ) 12 Hz), 7.31 (5H,
m), 7.53 (1H, d, J ) 12 Hz) ppm.; MS: (M+) 218, 189, 161, 131,
105, 59. Anal. Calcd for C14H22Si: C, 76.99; H, 10.15. Found: C,
76.89; H, 10.20.
Acknowledgment. Vivek Polshettiwar was supported, in part,
by the Postgraduate Research Program at the National Risk
Management Research Laboratory administered by the Oak
Ridge Institute for Science and Education through an interagency
agreement between the U.S. Department of Energy and the U.S.
Environmental Protection Agency.
a Reactions were performed at 50 °C with 4 mol % catalyst G-2 in
water. b Determined by 1H NMR spectroscopy and GC-MS. c GC yield.
d Mixture of products.
Experimental Section
Supporting Information Available: Experimental proce-
dures and NMR and MS data of the reported compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
A typical experimental procedure for olefin ring closing metath-
esis reaction follows: The diene (1 mmol) and Grubbs second
generation ruthenium catalyst (4 mol %) were added to a 10 mL
glass tube filled with 2 mL of water and the reaction mixture was
stirred for 2 h at 45 °C. After completion of the reaction, the reaction
JO801330C
J. Org. Chem. Vol. 73, No. 18, 2008 7419